The proposed research is designed to foster development of new pharmacological therapies for Rett syndrome (RTT), a severe and currently untreatable neurodevelopmental disorder with autistic features. RTT is a complex disorder affecting approximately 1 in 10,000 female births and is caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2)1,2, a transcriptional regulatory protein3. This proposal builds upon the recent discovery by Tonks and colleagues that PTPN1, the gene encoding protein tyrosine phosphatase 1B (PTP1B), is a transcriptional target of MeCP2 and is upregulated in RTT patients and Mecp2 mouse models. PTP1B is a critical enzyme that regulates multiple signaling pathways disrupted in RTT, including the protein tyrosine kinase TrkB, the high-affinity receptor for Brain Derived Neurotrophic Factor (BDNF)4. Studies by Katz and colleagues demonstrated that deficits in TrkB signaling are associated with neurologic dysfunction in RTT mouse models and that phosphorylation (activation) of TrkB is associated with symptom recovery5-7. Consistent with these results, the Tonks lab demonstrated that inhibition of PTP1B, using clinical stage molecules developed for other indications, is associated with increased activation of TrkB and other substrates, as well as improved neurological and metabolic function in RTT mice4. Together, these findings highlight PTP1B as a highly attractive target for the treatment of RTT. Therefore, the proposed studies are designed to evaluate the ability of two structurally and mechanistically distinct PTP1B inhibitors to improve neurologic function and structural synaptic defects in RTT mouse models. These studies will employ clinically relevant behavioral endpoints to enhance the translational potential of our findings and will be replicated in 2 different strains of Mecp2 mutant mice in two different laboratories to enhance the rigor and significance of our results. We will also identify downstream targets impacted by abnormal PTP1B signaling in RTT mice, not only to understand mechanisms underlying the therapeutic potential of PTP1B inhibitors but to also identify potential new therapeutic targets. These studies are designed to provide new insight into the therapeutic potential of PTP1B inhibitors for the treatment of RTT. Moreover, given the role of abnormal cell signaling in some genetic subgroups of autism, including abnormal phosphatase signaling (i.e., PTEN), it is hoped these studies will contribute to the development of effective treatments for other disorders on the autism spectrum as well.